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FDA Approves Prevymis to Prevent CMV Infection After Transplants
The FDA has approved letermovir (Prevymis, Merck) for the prevention of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant (HSCT). The medication will be available as once-daily tablets for oral use and as an injection for intravenous infusion.
CMV is a common and potentially serious viral infection in allogeneic HSCT recipients. CMV-seropositive patients who undergo an HSCT are at high risk for CMV reactivation. Any level of CMV infection is associated with increased mortality in HSCT patients.
In the pivotal phase 3 clinical trial supporting approval, significantly fewer patients in the letermovir group (38%, 122 of 325) compared with the placebo group (61%, 103 of 170) developed clinically significant CMV infection, discontinued treatment, or had missing data through week 24 post-HSCT (treatment difference: –23.5 [95% confidence interval, –32.5 to –14.6; P < 0.0001]), the primary efficacy endpoint.
All-cause mortality in patients receiving letermovir was lower compared with placebo, 12% versus 17%, respectively, at week 24 post-transplant. In this study, the incidence of bone marrow suppression in the letermovir group was comparable to the placebo group. The median time to engraftment was 19 days in the letermovir group and 18 days in the placebo group.
“Our findings demonstrate that letermovir is a significant and welcomed advance in the prevention of clinically significant CMV infection and lowers mortality in this highly vulnerable patient population,” said Dr. Francisco M. Marty, associate professor of medicine at Harvard Medical School and attending physician in transplant and oncology infectious diseases at Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston.
The recommended dosage of letermovir is 480 mg administered once daily, initiated as early as day 0 and up to day 28 post-transplantation (before or after engraftment), and continued through day 100 post-transplantation. If letermovir is coadministered with cyclosporine, the dosage of oral or intravenous letermovir should be decreased to 240 mg once daily. Letermovir is available as 240 mg and 480 mg tablets, which may be administered with or without food. It is also available as 240 mg and 480 mg injection for intravenous infusion via a peripheral catheter or central venous line at a constant rate over one hour.
Letermovir—the first new medicine for CMV infection approved in the U.S. in 15 years—is expected to be available in December. The list price (wholesaler acquisition cost) per day for letermovir tablets is $195.00 and for letermovir injection is $270.00. Wholesaler acquisition costs do not include discounts that may be paid on the product.
In trials, the cardiac adverse event rate (regardless of investigator-assessed causality) was higher in patients receiving letermovir than placebo (13% versus 6%). The most common cardiac adverse events were tachycardia (reported in 4% of letermovir patients and 2% of placebo patients) and atrial fibrillation (reported in 3% of letermovir patients and 1% of placebo patients). These adverse events were reported as mild or moderate in severity.
The rate of adverse events occurring in at least 10% of letermovir-treated HSCT recipients and at a frequency at least 2% greater than placebo were nausea (27% versus 23%), diarrhea (26% versus 24%), vomiting (19% versus 14%), peripheral edema (14% versus 9%), cough (14% versus 10%), headache (14% versus 9%), fatigue (13% versus 11%), and abdominal pain (12% versus 9%). The most frequently reported adverse event that led to study drug discontinuation was nausea (occurring in 2% of letermovir patients and 1% of placebo patients). Hypersensitivity reaction, with associated moderate dyspnea, occurred in one patient following the first infusion of IV letermovir after switching from oral letermovir, leading to treatment discontinuation.
Letermovir is contraindicated in patients receiving pimozide or ergot alkaloids. The concomitant use of letermovir and certain drugs may result in potentially significant drug interactions.
Among the more than 27,000 allogeneic HSCTs performed each year worldwide (including approximately 8,500 transplants in the United States), an estimated 65% to 80% of recipients have been previously exposed to CMV and are therefore at high risk for CMV infection. Without prophylactic measures, many patients undergoing allogeneic HSCT will experience CMV infection, which can cause a range of serious negative health outcomes in this population.
The FDA granted this application breakthrough therapy and orphan drug designations.